alpha-tocopherol dimer and process for its preparation



United States Patent i 3,173,927 u-TOCOPHEROL DlMER AND PROCESS FOR ITSPREPARATION Bonald R. Nelan, Rochester, N.Y., assignor to Eastman KodakCompany, Rochester, N.Y., a corporation at New Jersey No Drawing. FiledOct. 2, 1961, Ser. No. 142,623

11 Claims. (Cl. 260-3455) CH3 CH3 on, on CH H30 /CH2 /GE H CH2 CH1 CH3CH5 Hg CH3 CH3 CH3 This formula is usually written for the sake ofconvenience:

I o 0 n3 I C mHn EO- ot-Tocopherol occurs naturally in many vegetableand animal fats and oils. Processes have been developed to separatea-tocopherol in substantially pure form from these sources. u-Tocopherolis also synthesized by a process involving the reaction of trimethylhydroquinone with phytyl bromide. As a result a-tocopherol and certaincarboxylic acid esters thereof have become readily available commercialproducts.

A major use of these products is in vitamin preparations primarilybecause of their vitamin B activity. Antioxidant use is limited toa-tocOpherol inasmuch as a-tocopheryl esters have no significantantioxidant activity. While a-tocopherol is an effective antioxidant forfats and oils susceptible to oxidation, particularly vitamin Aconcentrates, the extent of antioxidant activity is not as great asother Well-known and readily available antioxidants. Consequently, thedemand for u-tocopherol for use as an antioxidant is small. Hence, thereis a need for an ot-tocopheryl compound of increased antioxidantactivity, particularly in oxidation susceptible fats and oils, ascompared to a-tocopherol.

An object of this invention is to meet this need.

More particularly, an object of this invention is to provide aderivative of a-tocopherol having greater antioxidant activity,especially for fats and oils, than 0:40- copherol itself.

These and other objects are achieved by this invention which, insummary, comprises a dimeric derivative of o:- tocopherol and a processfor making it. In addition, this invention comprises stabilized,oxidation susceptible fats and oils containing this derivative as anantioxidant.

3,173,927 Patented Mar. 16, 1965 The dimeric derivative of u-tocopherolof this invention has the following Formula I:

F- 1o 0 CH3 This compound, having the empirical formula C H O has atheoretical molecular Weight of 859.4. At normal room temperatures it isa light yellow oil. The infrared absorption spectra is similar to thatof a-tocopherol. A typical ultraviolet absorption measurement inisooctane is The acetate of this compound, prepared by treating it withacetic anhydride-pyridine mixture, is a solid having a melting point72-74" C. and has in ethanol a typical ultraviolet absorption spectrumof Elan, (27s m 287 m =4as, 51.7

The diquinone of the dimer of Formula I is a solid having a meltingpoint of 46 C. The a-tocopheryl dimer of Formula I has no vitamin Eactivity in the rat antisterility assay; however, it has antioxidantactivity, especially in oxidation susceptible fats and oils.Consequently, it has utility as an antioxidant.

The process for making the a-tocopherol dimer of this inventioncomprises the steps of oxidizing oc-tOCOPhGIOl with a ferricyanide underaqueous alkaline conditions whereby an m-tocopheryl oxidation product isformed, and then reducing the oxidation product with a mild reducingagent, such as, for example, ascorbic acid.

The first step of this process, oxidizing u-tocopherol with aferricyanide under aqueous alkaline conditions, is performed by admixingthe reactants, whereby a two phase mixture results.

The ferricyanide employed in the first step of this process is any watersoluble salt of ferricyanic acid containing the trivalent [Fe(CN).radical. Examples of such a salt are the alkali metal and alkali earthmetal fer ricyanides. A particularly effective and readily availableferricyanide is potassium ferricyanide.

The quantity of ferricyanide used in carrying out the first step ispreferably at least about 2 molecular equivalents or moles for each moleof a-tocopherol. The only upper limit on ferricyanide concentration isone of practicality.

Aqueous alkaline conditions are obtained by employing a Water solutionof a water soluble base as a medium in which to admix theOt-tOCOPllEl'Oi and ferricyanide. The base preferably is any alkalimetal or alkali earth metal hydroxide. Sodium hydroxide is especiallyuseful. The concentration of the base in the Water can vary within widelimits, the only important criterion being that the I O Ha reo- C iaHasO 2 \(EHZ /C mHaa H O O C Ha C H3 This compound upon isolation is ayellow oil having typical ultraviolet absorption spectra in isooctane ofThe infrared spectra of this compound in ether shows bands at 5.97, 6.03and 6.27 (indicating the presence of a carbonyl group and of conjugateddouble bonds) and at 7.96, 9.13 and 1036 Specific rotation of thecompound of Formula II, when prepared from d-a-tocopherol, is [a] Thetheoretical molecular weight of this compound which has the empiricalformula C H O is 857.4.

Preferably the oil phase of the two phase mixture is separated from thewater phase and purified prior to carrying out the second step of theprocess of this invention.

In passing it may be noted that Martins and Eilingsfeld, Ann., 607, 159(1957), have reported the oxidation of a-tocopherol with alkalinepotassium ferricyanide and the attempts made to characterize thecomposition of the oxidation product. However, Martins et a1. do notreport carrying out the second step of the process of this in vention.

The second step of the process of this invention, re ducing with areducing agent the oxidation product formed in the first step, isperformed by admixing the oxidation product with a mild reducing agent.A preferred reducing agent is ascorbic acid. However, other mildreducing agents such as one of the sulfhydryl compounds, for example:cysteine, can be used. The quantity of mild reducing agent present ispreferably at least the molecular equivalent of the major component ofthe oxidation product. Preferably the admixing is carried out in awater-alcohol system for the purpose of obtaining good contact betweenthe reactants. As a result of the admixing the a-tocopher-ol dimer ofFormula II is converted to the wtocopherol dimer of Formula I.Preferably, the a-tocopherol dimer of Formula I is separated from thereaction mixture and worked up to the extent desired for use asan'antioxidant.

This invention is further illustrated by the following examples ofvarious aspects thereof. This invention is not limited to the specificembodiments of the invention appearing in these examples unlessotherwise indicated.

Example 1 This example illustrates the preparation of the or-IOCOpheroldimer of Formula I.

4.0 grams of d-a-toco-pherol dissolved in 500 milliliters of petroleumether (boiling point 30-60 C.) were shaken in a separatory funnel with asolution of 10 grams potassium ferricyanide in milliliters of a 0.2 Nsodium hydroxide solution. A two phase mixture resulted, one phase beinga water solution and the other phase being a petroleum ether solution.The petroleum ether layer was separated, washed with water severaltimes, dried over anhydrous sodium sulfate and the petroleum ether thenremoved. There resulted 4.2 grams of a yellow oil having ultravioletabsorption spectra in isooctane of ny rsoo m,., 337 111,.) =43.6, 15.0

The yellow oil was chromatographed on a column of magnesium silicate(Florisil, 60-100 mesh U.S. screen size, Floridin Company). Thereresulted from this procedure 2.37 .grams of purified oxidation producthaving ultraviolet absorptions in isooctane of t't...(3 mu, 337 mu)=53.8, 22.1

1.3 grams of the purified oxidation product weredissolved in 20milliliters of ether. To this solution were admixed 160 milliliters ofethanol, 5 milliliters of water and 4 grams of ascorbic acid. Themixture was permitted to stand overnight at room temperature. 300milliliters of petroleum ether were then admixed therewith, giving a twophase mixture, one phase being a water solution, the other phase being apetroleum ether solution. The resulting petroleum other solution layerwas removed, washed with water, dried over anhydrous sodium sulfate,fdtered from the anhydrous sodium sulfate and evaporated to give a lightyellow oil. This oil in isooctane had an ultraviolet absorption of Ei'fi(297 mu) =76.7 Purification of this oil by chromatography on a column ofsodium aluminum silicate (Doucil, Philadelphia Quartz Company) gave 0.65gram of an oil product fraction having in isooctane iim. u)

E g ,(278 m 287 mu) =44.3, 51.7

The acetate ester of the d-tocopherol dimer of Formula I has theempirical formula C H O with a calculated theoretical molecular weightof 943.5, a carbon atom concentration of 78.9 weight percent and ahydrogen atom concentration of 10.9 weight percent. It was found uponmolecular weight determination by the aforementioned cryoscopic method,in benzene, that the acetic acid ester had a molecular weight of 972, acarbon content of 79.3 weight percent and a hydrogen content of 11.1percent.

The infrared absorption spectrum of the oil product was very similar tothat of a-tocopherol with a strong hydroxyl band (2.9g) and none in thecarbonyl region. When the spectrum was determined in carbon disulfidesolution, there was a smaller shift in location of the hydroxyl band (to2.85 1.) than occurs with or-tOCOpllGI'Ol (to 2.77u).

Hence, the oil product was the a-tocopherol dimer of Formula I.

Example 2 This example illustrates the antioxidant activity of theu-tocopherol dimer of Formula I of this invention and a comparison ofthis antioxidant activity with the antioxidant activity of a-tocopherol.

Samples of vitamin A palmitate containing the dimeric Ot-tOCOPhCI'Olproduct of Formula I at three different concentrations (0.5, 1.0 and 2.0weight percent) were prepared and compared in an accelerated stabilitytest with samples of the same vitamin A palmitate containing atocopherolat the same concentrations (0.5, 1.0 and 2.0 weight percent) and alsowith a sample of the same vitamin A palmitate containing no antioxidant.The accelerated stability test involved weighing a drop of each sampleon a strip of filter paper, storing the strips in an oven at 37 C. andassaying for the recovery of vitamin A after storage periods of 18 and24 hours.

The results of these stability tests are summarized in the followingtable.

Thus, the a-tocopheryl dimer of Formula I has much greater antioxidantactivity than a-tocopherol relative to vitamin A palmitate.

Thus, there is provided a new antioxidant and a process for itspreparation. A feature of advantage of this new antioxidant is its lowvolatility.

Other features, advantages and embodiments of this invention will occurto those in exercise of ordinary skill in the art upon reading theforegoing disclosure. All embodiments of this invention includingvariations and modifications embracing the spirit and essentialcharacteristics of this invention are within the scope of the claimedsubject matter unless specifically excluded by claim language.

I claim:

1. A composition of matter of the formula:

CH3 CH3 on; CH3 3H3 Hag fig 3 g cm on, on: on, ed. on, 01-13 (EH7 (1H3CH3 m it)? re s fi i I J CH2 CH2 CH2 C CH3 CH3 CH3 \O/ CH3 in:

2. A process for preparing an a-tocopheryl dimer of the formula:

(IJHQ CH3 on; CH3 (13H; e e is e f5 2 s I C 2 C CH2 CH2 CH2 CH2 CH};110- which comprises: oxidizing a-tocopherol with a Water solubleferricyanide salt whereby an oxidation product is formed; and reducingsaid oxidation product with a mild reducing agent selected from thegroup consisting of ascorbic acid and cysteine.

6 3. A process for preparing an a-tocopheryl dimer of the formula:

C Ha

I Cm H3 1 11a 3 gr /(EH ga /Cs /CI\g i CH3 CH CHg CH CH5 Cg 6H3 H0- H2H3 em out HO f g )5 )3 f3 5 CH1 CH3 CH5 CH7 CH3 CH3 CH3 H3O 0 CH3 CHwhich comprises: oxidizing a-tocopherol with a water solubleferricyanidc salt by admixing the same under aqueous alkaline conditionswhereby an oil-water mixture containing an oxidation product is formed;separating said oxidation product from said mixture; and reducing saidoxidation product with a mild reducing agent selected from the groupconsisting of ascorbic acid and cysteine.

4. A process for preparing an a-tocopheryl dimer of the formula:

3 CH3 0 CH3 1 113 CH3 CH )3 f5 f3 5 5 5 H CH2 CH2 CH3 Cg: CH5 CH3 whichcomprises: oxidizing cz-lIOCOPhCIOl with a water soluble ferricyanidesalt by admixing the same under aqueous alkaline conditions whereby anoil-water mixture containing an oxidation product is formed; separatingsaid oxidation product from said mixture; reducing said oxidationproduct with a mild reducing agent selected from the group consisting ofascorbic acid and cysteine by admixing said oxidation product with saidreducing agent in water and ethanol, whereby a reaction mixturecontaining said dimer is formed; and separating said dimer from saidreaction mixture.

5. A process for preparing an a-tocopheryl dimer of the formula:

CH3 CH3 CH3 CH3 I l we as is 2 s is re re CH1 CH2 CH2 CH2 CH2 CH2 CH HOwhich comprises: oxidizing u-tocopherol with potassium ferricyanide byadmixing the same under aqueous alkaline conditions whereby an oil-watermixture containing an oxidation product is formed; separating saidoxidation product from said mixture; reducing said oxidation prod netwith ascorbic acid by admixing said oxidation product with said ascorbicacid in water and ethanol, whereby a reaction mixture containing saiddimer is formed; and separating said dimer from said reaction mixture.

6. A process for preparing an a-tocopherol dimer of the formula whichcomprises: contacting an a-tocopherol dimer of the with a mild reducingagent selected from the group consisting of ascorbic acid and cysteine.

7. A process for preparing an u-tocopherol dimer of the formula I 3 CH3(3H3 11113 5 CH3 CH3 CH CH3 CH o E 5 f5 g E"/ E CH3 CH3 CH5 CH5 CH3 CH2CH3 H3C \O v CH CH3 3 which comprises: admixing an a-tocopherol dimer ofthe formula 3 CH3 CH CH with a mild reducing agent selected from thegroup consisting of ascorbic acid and cysteine in Water and ethanol,whereby a reaction mixture containing said dimer of the CH3 CH3 Cg, ME,

first formula is formed; and separating said dimer of the first formulafrom said reaction mixture.

8. A process for preparing an u-tocopherol dimer of the formula I 3 CH3E (3H3 Gm /O f3 f3 f3 f5 f5 {1 CH1 CH3 CH2 CHz CH: CH3 CH8 a CH; on 5 f5f 23 k5 CH; on; on: on

one

which comprises: admixing an a-tocopherol dimer of the formula 7 I 0 H3C C H CIIQ CH3 CH3 CH3 0: s/ s fie 2% re 2 CH; CH; CH1 CH3 CH2 CH7 CH3H;O

CH3 with ascorbic acid in water and ethanol, whereby a reaction mixturecontaining said dimer of the first formula is formed; and separatingsaid dimer of the first formula from said reaction mixture.

9. Stabilized, oxidation susceptible fats and oils containing as ananti-oxidant an tX-tOCOPheI'YI dimer of the formula:

CH3 CH3 CH 10. A stabilized, vitamin A composition consistingessentially of a vitamin A concentrate and as an antioxidant at aconcentration of at leastabout 0.5 weight percent of the composition anu-tocopheryl dimer of the formula:

OH I a 0 (3H3 CH3 EH CH B. Hacf5 )3 O, OH 0H CH, CH CH CH e m CH3 7H3 OHCH CH H CH: OH HO 9 a on, orr or1 orr, on, CH1 CH3 \O GHQ 11. Astabilized vitamin A palmitate composition consisting essentially ofvitamin A paimitate and as an antioxidant an a-tocopheryl dimer of theformula I 3 CH3 (3H3 CH3 CH3 H4 e f3)? R ofi, cm on, on 011, CH2 CH3 no(i311: (13H! :33 (13H; CH3 25 3 3 3 3 on. on. on. on, cm on, on,

I O CH: on3

at a concentration of at least about 0.5 Weight percent of thecomposition.

References fired by the Examiner UNITED STATES PATENTS 2,349,278 5/44Hickman 99-163X 1% 2,464,927 3/49 Hall et a1 99-16326; 2,526,865 10/50Gyorgy 99-163 X 2,592,628 4/52 Weisler 545.5 2,639,288 5/53 Bell et a1.260398.5 2,640,658 5/53 Weisler 26 )345.5 2,645,648 1/53 Evans et al.260398.5 2,680,749 6/54 Cawley et al 260-3455 OTHER REFERENCES Boyer:Journal American Chemical Society, vol. 73, pp. 733-740 (1951).

Issidorides: Journal American Chemical Society, vol. 73, pp.5146-5148(1951).

Martins et al.: Annalen der Chemie, vol. 607, pp. 159- 168 (1957).

Nelan et al.: Journal American Chemical Society, vol. 84, pp. 2963-2965(1962).

IRVING MARCUS, Primary Examiner".

NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners.

1. A COMPOSITION OF MATTER OF THE FORMULA:
 2. A PROCESS FOR PREPARING ANA-TOCOPHERYL DIMER OF THE FORMULA: